2-amino-4-piperidinoethyl-thiazole



Patented Apr. 21, 1953 i w UNITED STATES PATENT OFFICE Z-AMINO-4-PIPERIDINOETHYL-THIAZOLE James M. Sprague, Drexel Hill, and Anthony H.Land, Ridley Park, Pa., assignors to Sharp & Dohme, Incorporated,Philadelphia, Pa., a corporation of Maryland No Drawing. ApplicationOctober 10, 1947, Serial No. 779,214

1 Claim. (Cl. 260--293.4)

1 This invention relates to new derivatives of Example1.--2-amino-4-dimethylaminomeththiazole, which are useful asintermediates suitylthiozola-To a solution of 20 parts of dimethylablefor pr p rin th r compounds which m y amine in 30 parts of anhydrousethanol was addshow therapeutic application, and some of which ed 21.8parts of 2-amino-4-chloromethylthiazole thiazoles indicate variedefiectiveness as antihydrochloride. After standing overnight at room t yo ts T e new compounds of t e i temperature, the solution was heatedunder revention may be represented by the formula flux for A.; hour andwas then evaporated to dry- R ness under vacuum. The residue wasdissolved I H in 75 parts of water and made strongly alkaline K W with20% caustic soda solution, precipitating N R1 brown crystals, M. P.147-149 C., which on recrystallization from benzene gave pale yellowcrystals, M. P. 150-151.5 C.

Example 2.2-amino-4-diethylaminomethylin which Y represents the aminogroup NHz, or a substituted amino group in which one or both of theamino hydrogens is replaced by an alkyl,

aralkyl, aucycuc, or and group or groups or one 1 thiaeole.-5.5 parts of2-amino-4-chloromethylis replaced by an acyl group in which X reprethlazole hydrochloride 1n 40 parts of ethanol was sents or or a stirredvigorously while 66 parts of diethylamine group in which R2 represents alower allryl group, $2 5 g i fiifig g ggg gg gg ii fi gig R andregresent hydrogen or p aIZyl in about half an hour The next day thesolvent aralkyl ahcychc or alkenyl i m was removed by distillation invacuo The resi R. and R taken to ether consti u e ar a ring system as inpiieridine, morpholi ne, tetrad e was dissolved in dilute hydrochloricacid, the hydroquinoline, tetrahydroisoquinoline, and the sglutloln g i"fig; g g e if i like, and in which Z represents hydrogen or an f f a m6 alkyl group joined to one of the carbon atoms of u 8 was 6 ayers thegroup X to form a fused cyclic structure with mated the ether extractdljied with the thiazole radical as in the benzothiazole or dmus Sodmmsulfate- Evaporatlon of the ether tetrahydrobenzothiazole Structura lefta residue of oil which was dissolved in The new compounds of the presentinvention ml. of 6 M hydrochloric acid. The solution was may be preparedby reaction of thiourea, or a so made basic and extracted. Evaporationof the monosubstituted or unsymmetrical disubstituted ether extractagaln left an 011 that partially thiourea, with an alpha bromoketonewith ehmi lidified when stirred. Recrystallization from nation of andwater to form the thiazole hexane yielded sticky brown crystals. Thiswas Structure Compounds in which the group X dissolved in 16 parts ofisopropyl alcohol and the is may be conveniently prepared by solutionthen was saturated with hydrogen chloaction f an amine, particularly asecondary ride. Upon cooling, the solution deposited the amine, with gor 2 t t i white crystalline hydrochloride, M. P. 206-207cmm-omethylthiazole, which in n may be dec. Recrystallization from amixture of ethanol pared from alpha, gammwdicmomacetone and and ethylacetate yielded crystals, M. P. 206-207". thicurea or a monosubstltutedor unsymmetrical The free base was epa e from t e ydroc lodisubstitutedthi r Th acylamino ride and. after two recrystallisations from hexpoundsmay be prepared frgm the amino comane, white needles, M. P.63.5-64.5",were obtained. pounds by treatment with an acylating agent,as, Example 3 p o fi y for example, acetic anhydridapropionyl chloride,parts of D pe e W e ded to a acetyl chloride, benzoyl chloride or thelike, but Solution Parts O -ami110 ch1or0meth are advantageouslyprepared by the use of an ylthiazole hydrochloride in 80 parts ofanhydrous acylthiourea as an initial reactant. In general, alcohol.After standing at roo temperature any hydrocarbon groups present shouldnot ha re overnight, the alcohol was distilled in vacuo. in excess of 10carbon atoms, and, in the case The dark semi-solid residue w Suspendedin of the acyl compounds, the carbon linked chain ml. of water andacidified with hydrochloric of the acyl group should not have more thanacid to obtain a clear brown solution which was 7 carbon atoms.partially decolorized by two treatments with The preparation of the newcompounds will Norit. The addition of an excess of 20% sobe illustratedby the following examples, but the w dium hydroxide precipitated browncrystals of invention is not limited thereto. the aminothiazole. Thiswas dissolved in dilute hydrochloric acid, decolorized and precipitatedwith sodium hydroxide to give light yellow crystals, M. P. 158 161.Recrystallization from dilute alcohol gave material melting at 163.

Example 4.-2-amno-4-piperidinoethyl thiazole.1-bromol-piperidino-2butanone hydrobromide was prepared by adding 50 ml. of a 35% solution ofhydrogen bromide in glacial acetic acid to 34 g. of4-piperidino-2-butanone dissolved in 50 m1. of the same solvent. The hotsolution was stirred vigorously while 35 g. of bromine in 33 ml. ofglacial acetic acid was added dropwise, at a rapid rate. The addition of300 ml. of ipropyl ether precipitated a dark brown oil that soonsolidified. The solid was dissolved in boiling i-propyl alcohol and theresulting solution was partially decolorized by treatment with Darco. Oncooling, the solution deposited brown crystals, M. P. 154l56. Afterrepeated recrystallization from i-propyl alcohol, the product melted at157- 158". To a solution or 6.3 grams of this and 1.52 grams of thioureain'the minimum quantity of water was allowed to remain at roomtemperature for eighteen hours. The solution was partially decolorizedby treatment with Norit and then made alkaline with 20% sodium hydroxidesolution to precipitate yellow crystals; M. P. fi l-135 after threerecrystallizations from i-propyl ether. The dihydrochloride wasprecipitated by adding isopropyl ether to a solution of the base inethanolic hydrogen chloride. After repeated recrystallization fromi-propyl alcohol containing a little hydrogen chloride, the productmelted at 188-189".

' Example .-2-amino-4- (2- (1,2,3,4-tetrahg clroisoqainolz'no) -ethyl)-thiaaola-A solution of 7.35 grams of1-brorno-4-(1,2,3,4-tetrahydroisoquinolino) -2-butanone hydrobromide(prepared by bromination in glacial acetic acid of the correspondingketone hydrobromide) and 2 grams of thiourea were dissolved in 75 ml. ofwater containing 0.25 ml. of concentrated hydrochloric acid and left atroom temperature for sixteen hours. The filtered solution was madestrongly basic with aqueous sodium hydroxide. The semi-solid precipitatewas dissolved in isop-ropyl ether and the solution was dried withanhydrous sodium sulfate. Evaporation of the ether gave white crystals;M. P. 92-94", which turned brown within several days. A samplerecrystallized once from hexane and twice from i-propyl ether melted at93-935 The dihydrochloride, prepared in ethanol and precipitated withi-propyl ether, melted at 209-210 (dec.).

Example 6.--2-amino-4-dimethylaminomethyl- 4,5,6]tetrahydrobenaothiazoZe.-Dry hydrogen bromide was passed into a solutionof 25.5 g. of 2-dimethylaminomethylcyclohexanone in 150 m1. of i-propylether. The precipitated hydrobromide, M. P. 165-1655, was dissolved in100 ml. of hot glacial acetic acid and the solution was stirred andilluminated with a 75-watt lamp while g. of bromine in 20 ml. of aceticacid was added. After a few minutes the mixture set to a mass of whitecrystals. The solid was stirred with 350 ml. of i-propyl ether,filtered, suspended in 200 ml. of acetone, and filtered again; M. P.162- 163. Forty grams of the crude bromoaminoketone salt and 9.8 g. ofthiourea were dissolved in 100 ml. or" warm water containing 0.5 m1. of

concentrated hydrochloric acid. The solution then was heated on asteam-bath for one and one-half hours, cooled and made strongly alkalinewith 20% sodium hydroxide solution. The resulting suspension was shakenwith i-prOpYl ether and the extract was dried with anhydrous sodiumsulfate. Evaporation of the ether gave yellow crystals; M. P. 105407".Repeated crystallization from i-propyl ether gave white crystals; M. P.106-1075". An acetyl derivative was prepared by warming theaminothiazole with acetic anhydride in glacial acetic acid. The cooledsolution was neutralized with sodium hydroxide to precipitate the amidewhich melted at 179.5180, after repeated crystallization from 20%ethanol.

Example 7.2 amino 4 piperidinomethyl- 4,5,6]tetrahydrobenaothiazoZe.Eighty three grams of piperidine hydrobromide,200 g. of cyclohexanone and g. of 35% aqueous formaldehyde solution wereheated on a steam-bath for forty minutes, during which time the mixturebecame homogeneous. The cold, solid mixture was stirred with 300 ml. ofether, filtered and washed with ether; M. P. 133-184" (dec.) afterrecrystallization from isopropyl alcohol. Since furtherrecrystallization was accompanied by darkening and a decrease in meltingpoint, additional purification was not attempted. Eightythree grams ofthe aminoketone hydrobromide was dissolved in 300 ml. of glacial aceticacid and stirred while 48 g. of bromine in ml. of glacial acetic acidwas added. After the addition of a liter of i-propyl ether, stirring wascontinued until the oily precipitate of bromoketone salt solidified. Theyellow solid was washed with ether; M. P. about 145 (dec.).Recrystallization from isopropyl alcohol-ethyl acetate mixture did notproduce a sharply melting product. Twenty grams of the bromoketone and4.8 g. of thiourea were dissolved in ml. of water and, after two hours,the solution was heated on a steam-bath for one-half hour. The solutionthen was cooled, made basic with 20% aqueous sodium hydroxide. After thegummy yellow precipitate had solidified to a hard resinous mass, it waspulverized and washed with water. It then was suspended in boiling waterand dissolved by the gradual addition of ethanol. The solution wastreated with Darco and, upon cooling, deposited crystals, M. P.146-148". A second crop, M. P. 1455-1465, was obtained by adding waterto the mother liquor. After two crystallizations from a benzenehexanemixture, the melting point was 146.5-148 Example 8.2-amz'no-4-(Z-dimcthylaminoethyD-thiazoZafi parts ofl-bromol-dimethylamino-Z-butanone hydrobromide were added to a solutionof 12.2 parts of thiourea in 200 parts of water. The solution, which hadbecome warm, was allowed to remain at room temperature for 12 hours.After the solution had been partially decolorized by shaking it withdecolorizing carbon, an excess of 20% aqueous sodium hydroxide wasadded, whereupon the amine precipitated. After recrystallization fromisopropyl ether it melted at l28l29 C. The dihydrochloride was preparedby passing hydrogen chloride into an alcohol solution of the base andprecipitating the salt with isopropyl ether. This was recrystallizedfrom ethanol to a constant melting point of 139-lll C. witheffervescence.

Other compounds included within the invention, and which are readilyprepared by the procedures illustrated in detail in the foregoingexamples are: 7

2 methylaminol-morpholinornethylthiazole prepared from2-methylamino-l-chloromethylthiazole and morpholine;

2 ethylamino i dibenzylaminomethylthiazole, prepared from2-ethylamino--chloromethylthiazole and dibenzylamine;

2 benzylamino 4 diphenylamino-methylthiazole, prepared fromdiphenylamine and. 2- benzylamino-4-ch1or0methy1thiazo1e;

2 phenylamino 4 cyclohexylmethylaminomethylthiazole, prepared from2-pheny1amino-4- chloromethylthiazole and amine;

2 a-cetoamino 4 dimethylaminomethylthiazole, prepared from2-acetoamino-4-ch1oromethylthiazole and dimethylamine; and

2 benzoylamino 4 dimethylaminomethylthiazole, prepared from 2benzoylamino 4- chloromethylthiazole and dimethylamine.

5 cyclohexylmethyl- References Cited in the file of this patent UNITEDSTATES PATENTS Name Date Bock Oct. 22, 1946 OTHER REFERENCES Land et aL,J. Am. Chem. 800., vol. 68, pp. 2155- 2159 (1946).

Number

2.-AMINO-4-PIPERIDIOETHYL-THIAZOLE.